Hepatology Highlights
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Cure HCV If You Want to Live
Nicholas Russo and Robert S. Brown, Jr.1
Backus et al. aimed to evaluate the impact of direct-acting antiviral–induced sustained virological response (SVR) on all-cause mortality and on incident hepatocellular carcinoma (HCC) in 15,059 hepatitis C virus (HCV)-infected patients with advanced liver disease (ALD). Among patients with SVR versus those with no SVR, a 79% reduction in mortality rate and an 84% reduction in HCC rate were observed. In adjusted analyses, SVR was independently associated with reduced risk of death compared to no SVR (hazard ratio, 0.26). Though the potential for confounding may impact the overall magnitude of risk reduction, the benefits of SVR are increasingly clear, underscoring the important of timely treatment of all HCV-infected patients, especially those with ALD, who do not yet need transplant. (Hepatology 2019;69:487-497).
Et tu, TPL2: Inflammatory Signaling Through MKK7/JNK Promotes NAFLD
Shawn L. Shah* and Tibor I. Krisko1
Although nonalcoholic fatty liver disease (NAFLD) is frequently accompanied by obesity and insulin resistance, its pathogenesis remains incompletely understood. Tumor progression locus 2 (TPL2) is a serine/threonine kinase that influences a cascade of immune and inflammatory responses, with conflicting results in recent publications regarding its impact in metabolic disorders. In this study, Gong et al. found increased TPL2 expression in NAFLD patients as well as murine models of metabolic syndrome. Furthermore, in a diet-induced obesity murine model, hepatocyte-specific TPL2 knockout improved lipid and glucose homeostasis and decreased inflammation independent of weight, whereas overexpression of TPL2 led to the opposite phenotype. They found that TPL2 promoted hepatic steatosis (HS) by mitogen-activated protein kinase 7 (MKK7) and downstream c-Jun N-terminal kinase (JNK) activation, triggering hepatocyte and systemic metabolic dysfunction. Further experiments confirmed that TPL2 knockdown in genetically obese mice improved metabolic health. Future studies pharmacologically targeting this pathway as a NAFLD treatment are a meritorious goal. (Hepatology 2019;69:524-544).
HIF HIF Hooray! Another Target in the Fight Against NASH
Christopher S. Krumm** and Hayley T. Nicholls1
Hypoxia can activate hypoxia inducible factors (HIFs) that are able to influence hepatic lipid metabolism and promote hepatosteatosis, inflammation, and fibrosis in nonalcoholic steatohepatitis (NASH). Because accumulation and activation of macrophages in the liver are key features of NASH, Wang et al. investigated the macrophage-specific role of HIF-1a in the pathogenesis of this disease. Both HIF-1a and markers of autophagy were elevated in hepatic macrophages in murine NASH models and in monocytes from NASH patients. Macrophage specific stabilization of HIF-1a also impaired autophagic flux and exacerbated HS and inflammation in a murine NASH model. Comprehensive in vitro analysis using both murine- and human-derived macrophages demonstrated that saturated fatty-acid–induced impairment of autophagic flux was mediated by HIF-1a. Furthermore, HIF-1a promoted nuclear factor kappa B activation and consequent inflammation. This study identifies HIF-1a to be a critical modulator of macrophage proinflammatory activation and a promising target for further investigation in the management of NASH. (Hepatology 2019;69:545-563).
A Block and a Blast With a Hurricane of Bile
Omar Mousa,*** Harmeet Malhi,2 and Robert E. Schwartz1
The ascending pathophysiology of cholestatic liver disease suggests that downstream obstruction of bile ducts leads to cholestasis and bile-salt–mediated toxic injury of the “upstream” liver. Bile duct ligation (BDL) in rodents reflects obstructive cholestatic disease in humans, manifested by periportal fibrosis and increased blood concentration of bile salts. A further consequence of BDL is hepatocyte necrosis or “bile infarcts” attributed to bile leakage. Ghallab et al. evaluated the mechanisms of bile infarcts by performing BDL in healthy and cholestatic livers of anesthetized male mice. The investigators analyzed the mice up to 3 weeks and observed bile salt transport using intravital two-photon–based imaging with fluorescent bile salts. In the acute phase after BDL (first 3 days), there was increased bile salt concentration of bile and apical hepatocyte membrane rupture. This led to bile microinfarcts and necrosis of neighboring hepatocytes like “falling dominos.” Consequently, sinusoidal membranes became leaky, leading to a transient breach of the bile-to-blood barrier. Bile salts leak into the blood caused a drop in their concentration in the biliary tract, thereby protecting the liver from further bile salt toxicity. In chronic cholestasis (day 21 after BDL), reduced sinusoidal bile salt uptake is a protective factor for the liver at the expense of increased blood bile salt concentrations and cholemic nephropathy. An improved understanding of this pathophysiology is important to help develop better biomarkers and therapies for cholestatic diseases. (Hepatology 2019;69:666-683).
For PSC, We Still Haven’t Found What We’re Looking For
Zurabi Lominadze**** and Robert S. Brown, Jr.1
There are currently no effective medical therapies for primary sclerosing cholangitis (PSC). Targeting the pathways of hepatic fibrosis, such as that driven by the enzyme lysyl oxidase-like-2 (LOXL2), may be of benefit in arresting or reversing the progression of this disease. This international multicenter, randomized, double-blind, placebo-controlled, phase 2b dose-ranging study by Muir et al. tested the effect of the LOXL2 monoclonal antibody, simtuzumab, on hepatic collagen content, biopsy-proven fibrosis, and PSC-related clinical events in 234 patients with PSC for 96 weeks. Morphometric quantification of hepatic collagen in biopsy specimens at the end of therapy revealed no significant improvement with simtuzumab over placebo. Similarly, fibrosis did not significantly improve, except in the small subgroup of patients with elevated baseline immunoglobulin G4 who received simtuzumab. Clinical events, including ascending cholangitis (20%), hepatic decompensation, or cholangiocarcinoma (3%), occurred at the same rate for simtuzumab and to placebo. Multivariate analysis showed that baseline enhanced liver fibrosis (ELF) score and bridging fibrosis were associated with progression to cirrhosis, whereas baseline alkaline phosphatase level and advanced fibrosis were associated with development of PSC-related clinical events. Thus, though the study showed no benefit of simtuzumab, it added to our understanding of the natural history of PSC. (Hepatology 2019;69:684-698).
Overexpression SIRTain1y Protects From Cholestasis
Russell Rosenblatt**** and Robert E. Schwartz1
Sirtuin 1 (SIRT1) regulates liver regeneration and bile acid metabolism by modulating farnesoid X receptor (FXR). Blokker et al. investigated the role of SIRT1 in cholestasis and utilized SIRT1-overexpressing and hepatocyte-specific SIRT1 knockout mice, which were subjected to bile duct ligation (BDL) and were fed a 0.1% 3,5-diethoxycarboncyl-1,4-dihydrocollidine diet. Additionally, the effect of 24-norursodeoxycholic acid was tested in BDL/SIRT-overexpressing mice. SIRT1 was highly expressed in livers from cholestatic patients, mice after BDL, and Mdr2–/– animals. SIRT1 overexpression and hepatocyte-specific SIRT1 depletion correlated with inhibition of FXR. SIRT1 expression is increased during human and murine cholestasis. In summary, fine-tuning expression of SIRT1 provides a potential mechanism to protect the liver from cholestatic liver damage. (Hepatology 2019;69:699-716).
Under Pressure, Emricasan Screaming Let Me Out
Russell Rosenblatt**** and Brett E. Fortune1
Emricasan is a pan-caspase inhibitor that decreases portal hypertension (PH) and improves survival in murine models of cirrhosis. Garcia-Tsao et al. performed an exploratory analysis in a multicenter, open-label study to assess whether emricasan lowers PH (hepatic vein pressure gradient [HVPG] >5 mm Hg) in 23 patients with compensated cirrhosis. Emricasan was given twice-daily over 28 days, and HVPG was measured before and after. Most patients were Child class A, but 12 had severe PH (HVPG ≥12 mm Hg). HVPG decreased significantly in those with severe PH without changes to blood pressure or heart rate. Only 1 patient discontinued for a nonserious adverse event. In summary, emricasan offers the potential to reduce PH in patients without systemic hemodynamic changes, but further investigation is needed. (Hepatology 2019;69:717-728).
Angst About Angpt-2
Joseph F. Pisa and Arun B. Jesudian1
Patients with decompensated cirrhosis are at high risk developing hepatorenal syndrome and acute kidney injury (AKI) for which systemic inflammation and increased vascular permeability may play a role through the angiopoietin/Tie2 (Angpt-2) signaling axis. In a cohort of 191 inpatients with cirrhosis, 176 with AKI, Allegretti et al. serially measured Angpt-2 levels over a 90-day prospective period, ~40% of whom had AKI resolve. Those with improvement in AKI had lower initial Angpt-2 levels versus those who deteriorated. Similarly, patients who died had higher Angpt-2 levels than those who survived. After liver transplantation, Angpt-2 decreased, and among those that died, Angpt-2 levels increased. Thus, in the setting of cirrhosis and AKI, higher Angpt-2 levels were strongly associated with deteriorating status and mortality. Thus, Angpt-2 may represent a novel marker of vascular/systemic inflammation as well as a possible therapeutic target. (Hepatology 2019;69:729-741).
Biliary-Derived Hepatocytes? β Believe It!
Vikas Gupta* and Robert E. Schwartz1
Hepatocytes and biliary epithelial cells share a common developmental precursor known as the hepatoblast. Because of this, researchers have tested whether and how adult hepatocytes or biliary epithelial cells could be coaxed to transdifferentiate into their counterparts. β-catenin is required for hepatocytes to proliferate in response to injury. Russell et al. created mice with genetically induced hepatocyte specific β-catenin knockout and placed them on a choline-deficient, ethionine-supplemented diet, which causes liver injury. They found reduced proliferation of hepatocytes and increased liver injury after 2 weeks on this diet in mice with hepatocyte-specific β-catenin knockout. Mice that were subsequently placed on regular chow recovered from liver injury with new hepatocytes originating from biliary cells (upward of 70% of new hepatocytes!), verified with genetic lineage tracing. The plasticity of hepatocytes and biliary epithelial cells to compensate for each other underscores how interconnected these two populations are; a relationship that we all hope can be applied in the future to regenerative medicine. (Hepatology 2019;69:742-759).
Half a Day Back With Less NAC
Zaid H. Tafesh* and Robert S. Brown, Jr.1
Acetaminophen overdose is unfortunately common, but timely initiation of an acetylcysteine infusion can counter liver injury. Emerging data have suggested that abbreviating the 20-hour N-acetylcysteine (NAC) treatment regimen may be equally effective in low-risk patients. In this multicenter, cluster-controlled trial, Wong et al. compared a 12-hour and the standard 20-hour NAC infusion protocol in 100 low-risk acetaminophen overdose patients. Low-risk features included normal alanine aminotransferase (ALT) and creatinine on presentation and after 12 hours of treatment and an acetaminophen level within or under therapeutic range at 12 hours. Both groups of patients had similar excellent outcomes, with no significant difference in ALT and international normalized ratio at 20 hours and no reports of hepatic injury, more severe hepatotoxicity, or deaths. Therefore, identifying low-risk patients with acetaminophen overdose may allow decreased treatment time, shorter length of stay, and long-term cost saving, without sacrificing efficacy. (Hepatology 2019;69:774-784).
